Texas Children’s Hospital hosted the first ever family conference for the EBF3-HADDS (Hypotonia Ataxia Developmental Delays Syndrome caused by changes in the EBF3 gene) syndrome between July 25 – 27, 2019 in Houston, TX. The conference was organized by the EBF3-HADDS Foundation, a new nonprofit organization created in 2018 by families to promote awareness, research and support for this genetic syndrome.
The foundation’s founding Board of Directors include Dr. Ashley LeMaire, Mark LeMaire, Kelly Mastin, Paul Mastin, Mallory Schindler, and John M. Walton. EBF3-related HADD syndrome was co-discovered by Drs. Hsiao-Tuan Chao, Michael Wangler, Hugo Bellen, and their colleagues at the Undiagnosed Diseases Network, Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital, New York University Langone Health, and Baylor College of Medicine in 2016. Two other multi-national collaborative teams also published their findings concurrently in 2016.
Twenty-two families, totaling more than 70 people, from all over the U.S. and Canada attended the international conference in-person and 13 families from all over the world, including Ireland and Australia, participated via live-streaming services. Medical residents, genetics counseling students, and research scientists were also in attendance. The conference included presentations on a wide variety of topics related to EBF3-HADD syndrome from physician-scientists, Drs. Hsiao-Tuan Chao, Michael Wangler, Irina Stanasel; genetic counselor, Pilar Magoulas; and patient advocate, Geraldine Bliss, research director of the Phelan-McDermid Foundation who provided valuable guidance. In addition, patients received clinical evaluations by Chao and Wangler. All attendees were also able to tour various laboratories and research facilities at the NRI where one of the first genetic mutations related to this syndrome was discovered in 2016 and the first research lab (Chao’s) devoted to understanding the biology of this disorder is located.
Investigation into this disorder was first initiated in 2016 in the Bellen lab by Chao and Wangler when they received a puzzling case from the National Institute of Health’s Undiagnosed Diseases Program, a part of the Undiagnosed Diseases Network. The child, Chase Kaya, presented with impaired speech and cognition, low muscle tone, balance/gait issues, reduced ability to feel physical pain, and lacked the ability to display strong facial emotional expressions such as a smile, laugh or cry. Although the child’s and his parents’ DNA was sequenced six years earlier and a few genes were identified as candidates, without a cohort of similarly-affected patients or experiments in animal models, it was impossible to determine which one of those genes was responsible for his symptoms. So, the patient and his family continued to search for a diagnosis for years.
To find an answer for this patient, researchers selected the most likely candidate gene from that list, EBF3. Since very little was known about the biological role of EBF3, Chao generated fruit fly models that mimicked the patient’s mutation to better understand its function. Luckily, within a few months, they found three other patients with similar motor, cognitive, and sensory issues with similar alterations in the EBF3 gene. Read this blog about one of those patient’s diagnostic odyssey.
By 2017, the LeMaire family, whose child has EBF3-HADDS, formed a family group on Facebook in order to create a community of support. This group has grown over the past two years into a close-knit international community of over 100 members, who were the driving force behind the creation of the EBF3-HADDS foundation, the inaugural EBF3-HADDS family conference, and the EBF3-HADDS public community Facebook page. “Our HADDS community is a motivated and talented group of families dedicated to supporting research, education, and advocacy efforts for HADDS patients and support each other on this journey,” said Ashley LeMaire, board member of the EBF3-HADDS Foundation.
Currently, there are 30 EBF3-HADD syndrome cases reported in the literature and more than 200 patients identified worldwide with EBF3-HADD syndrome. The majority of the cases appear to result from spontaneous mutations in EBF3 and children of both genders are equally vulnerable. “As we learn more about symptoms characterizing this condition, and as more physicians become aware and get their patients tested for damaging changes in the EBF3 gene, we expect these numbers to increase significantly. Neurologic and psychiatric effects of alterations in the EBF3 gene could be more widespread in the population than we thought originally,” Chao said.
Based on these cases, it appears that while some EBF3 patients may have variable intellectual or cognitive issues, many are at age-appropriate cognition. “Sometimes because they are unable to make strong facial expressions, their cognitive capabilities may remain underappreciated. However, we find these children often have the capability to learn at the same level as their peers, and adults who are diagnosed with milder forms of this condition are able to lead independent lives, hold jobs, and have families,” Chao said.
“The gene discovery story of EBF3 illustrates the ‘Power of One’ in medicine and biomedical research. How a single patient with an undiagnosed disorder (a ‘medical mystery’) can lead to the discovery of the gene responsible for a previously unknown disorder. This becomes the starting point to develop the diagnostic tests and therapies that can transform the lives of many patients and their families. Another crucial practical benefit for patients and their families who receive a genetic diagnosis for a previously unknown condition is these patients can more easily qualify for disability services, therapies and other medical interventions. They also become part of a supportive and growing patient and family community,” Chao added.
Drs. Chao and Wangler have offered monthly clinical evaluations for EBF3-HADD syndrome patients at Texas Children’s since 2017. Together, they have now seen the largest number of EBF3-HADD syndrome patients in a single institution worldwide. They are also enrolling patients in an EBF3-HADD syndrome natural history study to better understand the condition and to assist in translating research endeavors into clinical interventions.
This first-of-its-kind conference is a testament to the power of teamwork and collaboration – of how a group of committed researchers at Texas Children’s, the NRI, and from around the world identified the gene responsible for this condition, which led to the establishment of the first clinic at Texas Children’s and the first research team at NRI dedicated to EBF3-HADD syndrome. Most importantly, it shows how a dedicated parents and volunteers came together within two years of the EBF3-HADDS discovery to form a community, build a foundation, and organize this conference for the benefit of current and future patients and families.
“The conference was the first time most of the patients and their families had met another person with this syndrome. After years of feeling isolated, they were now suddenly in a room with 22 other children with HADDS syndrome and their families. It was beautiful to see these children making new friends and parents instantly bonding with one another. This is why we recommend families of other rare disorders to connect with each other and harness the power of social media to form supportive communities. Besides offering crucial social and emotional support, it offers several other practical benefits - having a cohort of patients allows researchers to rapidly catalog the symptoms and their severity, understand the disease trajectory, and quickly identify potential complications. We realized what began as an intellectual curiosity to understand the biology of EBF3 had in such a short time given rise to this wonderful community. It was incredibly heart-warming to witness this growth and transformation. No longer are the families alone in this journey. They share their experiences and learn together, and we are in this journey with them as physicians and as researchers dedicated to EBF3-HADD syndrome. It is this ability to change peoples’ lives for the better that inspires and motivates my team every single day. At the moment, we can only offer supportive therapies, but our goal is to develop targeted treatments for EBF3-HADDS in the future,” Chao said.
“There is still much to learn about HADDS, but when you have such a dedicated team of physicians and researchers collaborating with families to learn about the condition and provide needed support, it fosters so much hope for our families. The HADDS clinic visits are universally seen by our families as an indispensable experience, as it empowers them with knowledge about HADDS that they can then share with their local providers, therapists, and educators.” LeMaire concluded.
For clinical consultations with Drs. Chao and Wangler in the EBF3-HADDS clinic, contact Marcus Brisker-Richardson at Texas Children’s Neurology Clinic (832-822-2778).